Certain folic acid antimetabolites are known to be antineoplastic agents. These compounds inhibit enzymatic conversion involving metabolic derivatives of folic acid. One such compound described by U.S. Pat. No. 5,344,932, known as “Pemetrexed” represented by Formula I (shown below), is currently formulated into a concentrated liquid for administration as an infusion dosage form. This member of the folic acid family has been approved for treatment of malignant pleural mesothelioma and for second-line treatment of non small cell lung cancer. Pemetrexed disodium heptahydrate salt represented by Formula II is marketed by Eli Lilly and Company under the trade name ALIMTA® as a sterile lyophilized powder for intravenous administration. The commercial product is reported to be a lyophilized powder of heptahydrate pemetrexed disodium and mannitol. The lyophilized product is available in strengths of 100 mg/vial and 500 mg/vial and is reconstituted with 0.9% sodium chloride at a concentration of 25 mg/mL before its administration.

The teachings of U.S. Pat. No. 5,344,932 provides that the compounds claimed therein can be administered parenterally.
It was found that a simple, isotonic saline solution of pemetrexed is not pharmaceutically acceptable for commercial purposes due to degradation of the solution to form unacceptable related substances. The chemical instability of pemetrexed is mainly attributed to their oxidative and acidic degradation.
Bernd et al., in U.S. Pat. No. 6,686,365 discloses a stable ready-to-use (RTU) formulation of pemetrexed which is developed by using antioxidants/amino acids like L-cysteine, monothioglycerol and thioglycolic acid. The preferred salt of the Pemetrexed is clearly mentioned as Pemetrexed disodium with at least one antioxidant. The formulation disclosed is an aqueous one.
Yanling et al., in CN Patent No. 101081301, again discloses a stable ready-to-use (RTU) formulation of pemetrexed stabilized by using antioxidant like L-arginine, L-glutathione, L-methionine and L-tryptophan. The preferred salt of the pemetrexed is clearly mentioned as Pemetrexed disodium with at least one antioxidant
Palepu et al., in PCT Application Publication No. WO2012/015810, claims a RTU solution formulation of pemetrexed along with an antioxidant, a chelating agent and dissolved in a pharmaceutically acceptable fluid. The preferred salt is pemetrexed disodium.
Chandrasekhar et al., in U.S. Patent Application Publication No. 20110201631, discloses lyophilized formulations of amorphous pemetrexed and its salts and the preferred one is disodium salt of pemetrexed. The amorphous form of pemetrexed is particularly referred in this patent application.
It is indicated from all the above-mentioned prior art that all the pharmaceutical compositions of pemetrexed utilizes the preferred salt of pemetrexed which is pemetrexed disodium. Antioxidants are also used in the prior art compositions. Further all of the above mentioned prior art compositions are aqueous-based.
Further, U.S. Patent Application Publication No. 20080139810 discloses a process for preparing disodium salt of Pemetrexed, wherein the starting material is pemetrexed of Formula I. The pemetrexed thus utilized is converted to pemetrexed disodium of Formula II during lyophilization process. Hence, there is in situ formation of pemetrexed disodium during lyophilization and the final product contains pemetrexed disodium.
In light of the above mentioned prior arts there remains a need to develop stable parenteral pharmaceutical compositions of pemetrexed of Formula I. In the present invention it was surprisingly found that pemetrexed according to Formula I containing pharmaceutically acceptable organic amines and an inert gas are favorable in formulating pharmaceutical compositions for medical use.
Further, controlling oxygen content with inert gas purging and/or using antioxidants, chelating agents, amino acids and maintaining higher pH values using pharmaceutically acceptable organic amines is useful in controlling the oxidative and acidic degradation of pemetrexed.
The present invention provides the composition of pemetrexed with pharmaceutically acceptable organic amine which is free of sodium ions of disodium salt of pemetrexed released during the dilution of the pharmaceutical composition of pemetrexed disodium and uses pharmaceutically acceptable organic amines to control the acidic degradation.
Against this backdrop of oxidative and acidic degradation, the inventors of the present application have surprisingly found that stable pharmaceutical compositions of pemetrexed can be developed by utilizing pemetrexed along with a pharmaceutically acceptable organic amine and may optionally contain some other pharmaceutically acceptable excipients.